Typically, Hirschsprung's disease is diagnosed shortly after birth, although it may develop well into adulthood, because of the presence of megacolon, or because the baby fails to pass the first stool (meconium)[3] within 48 hours of delivery. Normally, 90% of babies pass their first meconium within 24 hours, and 99% within 48 hours. Other symptoms include green or brown vomit, explosive stools after a doctor inserts a finger into the rectum, swelling of the abdomen, lots of gas and bloody diarrhea.

Some cases are diagnosed later, into childhood, but usually before age 10.[3] The child may experience fecal retention, constipation, or abdominal distention.[3] With an incidence of one in 5,000 births, the most cited feature is absence of ganglion cells: notably in males, 75 percent have none in the end of the colon (recto-sigmoid) and eight percent lack ganglion cells in the entire colon. The enlarged section of the bowel is found proximally, while the narrowed, aganglionic section is found distally, closer to the end of the bowel. The absence of ganglion cells results in a persistent over-stimulation of nerves in the affected region, resulting in contraction.

In some extremely rare cases, the absence of ganglion cells continues to spread after the corrective surgery, resulting in multiple surgeries.

Those patients that also have thyroid cancer may be able to digest food properly, but may not be able to use the nutrients properly.

The most accepted theory of the cause of Hirschsprung is that there is a defect in the craniocaudal migration of neuroblasts originating from the neural crest that occurs during the first 12 weeks of gestation. Defects in the differentiation of neuroblasts into ganglion cells and accelerated ganglion cell destruction within the intestine may also contribute to the disorder.[4]

This lack of ganglion cells in the myenteric and submucosal plexus is well-documented in Hirschsprung's disease.[3] With Hirschsprung's disease, the segment lacking neurons (aganglionic) becomes constricted, causing the normal, proximal section of bowel to become distended with feces. This narrowing of the distal colon and the failure of relaxation in the aganglionic segment are thought to be caused by the lack of neurons containing nitric oxide synthase.[3]

The RET proto-oncogene accounts for the highest proportion of both familial and sporadic cases, with a wide range of mutations scattered along its entire coding region.[7] A proto-oncogene is a gene that can cause cancer if it is mutated or over-expressed.

Research published in 2002 suggested that Hirschsprung's may be caused by the interaction between two proteins encoded by two variant genes. The RET proto-oncogene on chromosome 10 was identified as one of the two genes involved. The other protein that RET must interact with in order to cause Hirschsprung’s disease is termed EDNRB, and is encoded by the geneEDNRB located on chromosome 13.

RET is a gene that codes for proteins that assist cells of the neural crest in their movement through the digestive tract during the development of the embryo. Those neural crest cells eventually form bundles of nerve cells called ganglions. EDNRB codes for proteins that connect these nerve cells to the digestive tract. Thus, mutations in these two genes could directly lead to the absence of certain nerve fibers in the colon. Research published in June 2004 suggests that there are several genes associated with Hirschsprung’s disease.[8] Also, new research suggests that mutations in genomic sequences involved in regulating EDNRB have a bigger impact on Hirschsprung’s disease than previously thought.

RET can mutate in many ways and is associated with Down syndrome. Since Down Syndrome is comorbid in two percent of Hirschsprung’s cases, there is a likelihood that RET is involved heavily in both Hirschprung's disease and Down Syndrome. RET is also associated with medullary thyroid cancer and neuroblastoma, which is a type of cancer common in children. Both of these disorders are more common in Hirschsprung’s patients than in the general population. One function that RET controls is the travel of the neural crest cells through the intestines in the developing fetus. The earlier the RET mutation occurs in Hirschsprung’s disease, the more severe the disorder becomes.

Common and rare DNA variations in the Neuregulin 1 (NRG1) and NRG3 (NRG3) were first shown to be associated with the disease in Chinese patients through a Genome Wide Association Study (GWAS) by the Hong Kong team in 2009 [9] and 2012 respectively[10] Subsequent studies in both Asian and Caucasian patients confirmed the initial findings by the University of Hong Kong. Both rare and common variants in these two genes have been identified in additional Chinese,[11] Thai, Korean, Indonesian and Spanish patients. These two genes are known to play a role in the formation of the enteric nervous system, thus, they are likely to be involved in the pathology of Hirschsprung, at least in some cases.

Definitive diagnosis is made by suction biopsy of the distally narrowed segment.[12] A histologic examination of the tissue would show a lack of ganglionic nerve cells. Diagnostic techniques involve anorectal manometry,[13]barium enema, and rectal biopsy. The suction rectal biopsy is considered the current international gold standard in the diagnosis of Hirschsprung's disease.[14]

Radiologic findings may also assist with diagnosis.[15]Cineanography (fluoroscopy of contrast medium passing anorectal region) assists in determining the level of the affected intestines.

The first stage of treatment used to be a reversible colostomy. In this approach, the healthy end of the large intestine is cut and attached to an opening created on the front of the abdomen. The contents of the bowel are discharged through the hole in the abdomen and into a bag. Later, when the child’s weight, age, and condition are right, the "new" functional end of the bowel is connected with the anus. The first surgical treatment involving surgical resection followed by reanastomosis without a colostomy occurred as early as 1933 by Doctor Baird in Birmingham on a one-year-old boy.

Orvar Swenson, who discovered the cause of Hirschsprung’s, first performed its surgical treatment, the pull-through surgery in 1948.[16] The pull-through procedure repairs the colon by connecting the functioning portion of the bowel to the anus. The pull-through procedure is the typical method for treating Hirschsprung’s in younger patients. Swenson devised the original procedure, and the pull-through surgery has been modified many times.

Currently, there are several different surgical approaches, which include the Swenson, Soave, Duhamel, and Boley procedures. The Swenson procedure leaves a small portion of the diseased bowel. The Soave procedure leaves the outer wall of the colon unaltered. The Boley procedure is a small modification of the Soave procedure, so the term "Soave-Boley" procedure is sometimes used.[17][18] The Duhamel procedure uses a surgical stapler to connect the good and bad bowel.

For the 15 percent of children who do not obtain full bowel control, other treatments are available. Constipation may be remedied by laxatives or a high fiber diet. In those patients, serious dehydration can play a major factor in their lifestyle. A lack of bowel control may be addressed by a stoma, similar to a colostomy. The Malone antegrade colonic enema (ACE) is also an option.[19] In a Malone ACE, a tube goes through the abdominal wall to the appendix or, if available, to the colon. The bowel is then flushed daily.[20] Children as young as 6 years of age may administer this daily flush on their own.

If the affected portion of the lower intestine is restricted to the lower portion of the rectum, other surgical procedures may be performed, such as a posterior rectal myectomy.

The prognosis is good in 70 percent of cases. Chronic post-operative constipation is present in 7 to 8 percent of the operated cases. Post-operative enterocolitis is a severe manifestation that is present in the 10%–20% of operated patients.

According to a 1984 study conducted in Maryland, Hirschsprung's disease appears on 18.6 per 100,000 live births.[27] In Japan, Hirschsprung disease occurs at a similar rate of about one in 5,000 births (20 per 100,000).[28] It is more common in male rather than female (4.32:1) and in white rather than non-white.[29] Nine percent of the Hirschsprung cases were also diagnosed as having Down syndrome.[27] Most cases are diagnosed before the patient is 10 years of age.[3]

The first publication on an important genetic discovery of the disease was from Martucciello Giuseppe et al. in 1992. The authors described a case of a patient with total colonic aganglionosis associated with a 46, XX, del 10 (q11.21 q21.2) karyotype.[34] The major gene of Hirschsprung disease was identified in this chromosomal 10 region, it was the RET proto-oncogene.[35]

The usual treatment is "pull-through" surgery where the portion of the colon that does have nerve cells is pulled through and sewn over the part that lacks nerve cells (National Digestive Diseases Information Clearinghouse). For a long time, Hirschsprung’s was considered a multi-factorial disorder, where a combination of nature and nurture were considered to be the cause. However, in August 1993, two articles by independent groups in Nature Genetics said that Hirschsprung’s disease could be mapped to a stretch of chromosome 10.[36][37]

This research also suggested that a single gene was responsible for the disorder. However, the researchers were unable to isolate it.